INHIBITORS OF PROTEIN PRENYLTRANSFERASES
The present invention is directed to novel compounds. These compounds can be useful in inhibiting the activity of protein prenyltransferases including GGTase I and/or RabGGTase. The compounds can also be used as anti-cancer therapeutics including as part of methods for treating cancer, in assays, and in kits.
1 . A compound having the formula
wherein J is hydrogen or is 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, OR′, SR′, and NR′ 2 , where R′ is alkyl,
wherein G is
wherein E is hydrogen or is 1-2 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, OR′, SR′, and NR′ 2 , where R′ is alkyl,
wherein W is selected from the group consisting of hydrogen, cyclic, linear, or branched alkyl of from 2 to 8 carbons, unsubstituted phenyl, and phenyl substituted with C 1 -C 3 alkyl, halogen; OR′, SR′, and NR′ 2 , where R′ is alkyl,
wherein
is selected from the group consisting of
wherein A is selected from the group consisting of:
wherein M is selected from the group consisting of OH, OR″, NH 2 , NHOH, NHOR″, wherein R″ is methyl or ethyl, or any other group that has a polar metal binder
wherein R corresponds to an alpha-substituent of natural or non-natural alpha-amino acid;
wherein Z is S-U; and
wherein U is selected from the group consisting of alkyl having 10 or fewer carbons, phenyl, optionally substituted with halogen or OR″, wherein R″ is methyl or ethyl, and (CH 2 ) n —COOR 4 , wherein n=1-4 and R 4 is a linear or branched alkyl having four or fewer carbons.
2 . A compound of claim 1 , wherein A is
3 . A compound of claim 1 , wherein A is
4 . A compound of claim 1 , wherein A is
5 . A compound of claim 1 , wherein A is
6 . The compound of claim 2 , wherein M is OEt, OMe, Ot-Bu, OH, NH 2 , NHOH, NHOMe, or any other groups that have a polar metal binder.
7 . The compound of claim 1 , wherein the compound is selected from the group consisting of P61-A6, P61-A7, P61-A5, P61-B4, and P61-B6.
8 . The compound of claim 1 , wherein the compound is selected from the group consisting of P8-G7, P8-H6, P8-H7, and P49-F5.
9 . The compound of claim 1 , wherein the compound is selected from the group consisting of P23-D6, P47-D11, P49-A6, P49-F6, and P50-E11.
10 . The compound of claim 1 , wherein G is
11 . The compound of claim 1 , wherein the compound inhibits the activity of a protein prenyltransferase.
12 . The compound of claim 1 , wherein the compound inhibits the activity of a RabGGTase.
13 . The compound of claim 1 , wherein the compound inhibits the activity of GGTase I.
14 . The compound of claim 1 , wherein the compound inhibits the activity of GGTase I and RabGGTase.
15 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
16 . A method comprising administering the compound of claim 1 to a cell in an amount sufficient to inhibit the activity of GGTase I and/or RabGGTase.
17 . The method of claim 16 , wherein the compound is administered at a micromolar concentration.
18 . A method comprising administering a compound of claim 1 in an amount sufficient to inhibit the growth of a cancer cell or to reduce the size of a tumor of cancer cells.
19 . (canceled)
20 . The method of claim 18 , wherein the cancer cell comprises GGTase I and/or RabGGTase modified proteins.
21 . A method comprising administering to a subject in need of treatment for a cancer the pharmaceutical composition of claim 15 in an amount sufficient to inhibit the activity of a protein prenyltransferase.
22 . (canceled)
23 . The method of claim 21 , wherein the protein prenyltransferase is GGTase I, RabGGTase, or both.
24 . The method of claim 21 , wherein the cancer cell comprises GGTase I and/or RabGGTase modified proteins.
25 . A method comprising measuring the GGTase I and/or RabGGTase inhibiting activity of a compound of claim 1 .
26 . A method of preparing a compound according to formula I
wherein:
wherein J is hydrogen or is 1-2 substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, OR′, SR′, and NR′2, where R′ is alkyl,
wherein W is selected from the group consisting of hydrogen, cyclic, linear, or branched alkyl of from 2 to 8 carbons, unsubstituted phenyl, and phenyl substituted with C 1 -C 3 alkyl, halogen, OR′, SR', and NR12, where R′ is alkyl,
G is
wherein E is hydrogen or is 1-2 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, OR′, SR′, and NR′ 2 , where R′ is alkyl,
is selected from the group consisting of
wherein A is
and M=OH, OR, or NH 2 ; and R is, an alpha-substituent of a natural or non-natural amino acid;
comprising,
reacting a compound according to formula I′
wherein
J, G, and W are as defined above and
is selected from the group consisting of
wherein A=CO 2 H;
with a compound having the formula
wherein R and M are as defined above.
27 - 31 . (canceled)